Abstract In the proposed project, Tioga Research, in cooperation with DMK Pharmaceuticals, aims to firmly establish the feasibility of Trikamed?, a transdermal patch for the delivery of the novel mixed opioid receptor agonist, DPI- 125, as an alternative to current options for the relief of moderate to severe chronic pain. Tioga Research will leverage its huge database of molecular penetration enhancer (?MPE??) performance and draw from its vast experience with transdermal patch innovations to generate prototype DPI-125 transdermal patches. Immediate stability and DPI-125 skin permeation will be measured and prototype patches will then be optimized for stability, drug delivery and adhesion. The project will conclude with an in vivo study in Gttingen mini pigs to assess systemic delivery, pharmacokinetics and skin irritation at the patch application site. Abuse of, and addiction to opioids such as heroin, morphine and prescription pain killers is a massive problem, affecting health and social & economic welfare worldwide. Despite advances in the management of chronic pain, no non-opioid drug is effective enough to combat severe pain. Most patients with chronic pain are still prescribed opioid analgesics, despite doctors' increasing hesitance due to concerns of misuse, abuse or diversion. Prescription opioid medicines, such as morphine, fentanyl and hydrocodone produce their therapeutic benefit as well as their addictive and adverse effects by selectively binding to and activating mu-opioid receptors. In con- trast, DPI-125 acts like the body?s natural opioid peptides, enkephalin, endorphin and dynorphin, in that it is an agonist at all 3 principal opioid receptors: mu, delta and kappa. DPI-125 is a new chemical entity designed to have an improved safety profile and broader therapeutic index than current opiates. No other drug like DPI-125 (mu, kappa and delta mixed agonist) is currently on the market or in development. DPI-125 has demonstrated strong antinociceptive activity in non-clinical models of acute pain. In preclinical mod- els, compared to mu analgesics, DPI-125 showed reduced potential for respiratory depression, nausea, consti- pation and urticaria in rodents and substantially reduced abuse potential in non-human primates. In a study conducted by NIH with rhesus monkeys, DPI-125 was found to be 30-fold less potent in reinforcing effects than alfentanil and 30% less active than alfentanil in terms of these reinforcing effects. In a randomized, single-center, double-blind, placebo-controlled, dose-escalating Phase 1 study in human subjects, intravenous DPI-125 was well-tolerated with no findings of clinical concern at any dose tested. These data indicate that DPI-125 will have analgesic benefits at least comparable to that of morphine and fen- tanyl but with a far better tolerability profile; it offers a larger safety margin for respiratory depression and signif- icantly reduced abuse potential. The transdermal patch format for DPI-125, Trikamed?, will optimize the dosing profile, boost patient compliance and discourage abuse attempts. Trikamed? could thus represent a step-out alternative to current opioid analgesics, with the potential to replace a large proportion of the opioid market.